Membrane proteins (MPs) play crucial roles in biology, but these proteins are difficult to handle and analyze because of their physical properties. The native conformations of MPs display extensive nonpolar surfaces. The display of these nonpolar surfaces is necessary for residence in a lipid bilayer but leads to denaturation and/or aggregation in an aqueous medium. Detergents such as dodecyl-β-D-maltoside (DDM) are typically employed to render MPs soluble by coating the nonpolar protein surfaces. However, only some MPs can be maintained in native-like conformations when solubilized with conventional detergents (Serrano-Vega et al., Proc. Natl. Acad. Sci. USA 2008, 105, 877-882). Moreover, even when a native conformation can be achieved, the MP-detergent complex may manifest unfavorable properties with regard to structural analysis, such as the inability to crystallize and/or the formation of complexes too large for NMR analysis. Because our understanding of membrane protein structure and function remains poorly developed relative to soluble proteins, there is a persistent need for new amphiphilic “assistants” that can promote solubilization and manipulation of MPs.
Several groups have reported creative implementations of the “facial amphiphile” concept for the design of novel amphiphiles that display favorable behavior with selected membrane proteins (see for example, Cheng et al., J. Am. Chem. Soc. 1992, 114, 7319-7320; Schafineister et al., Science 1993, 262, 743-738). For example, McGregor et al. reported lipopeptides that are intended to match the width of a lipid bilayer and form a sheath around nonpolar surfaces of MPs (Nat. Biotech. 2003, 21, 171-176). Zhang et al. have developed cholate-based amphiphiles in which hydrophilic maltose units project from one side of the rigid and hydrophobic steroidal skeleton (Angew. Chem. Int. Ed. 2007, 119, 7153-7155). While these approaches promote the solubilization and aid the manipulation of some MPs, they are not universally effective for all MPs.
Accordingly, there is a need for new amphiphiles for the solubilization of MPs. There is also a need for new amphiphiles that aid the isolation and manipulation of MPs, such as amphiphiles that approximate the width of a lipid bilayer to form a sheath around nonpolar surfaces of MPs, and amphiphiles that can help to maintain the MPs in native-like conformations when solubilized.